Our program of research has been designed around the premise that breaking the cycle of intergenerational alcoholism could be best achieved by intervening in the lives of high-risk children before alcohol abuse becomes entrenched in their life-styles. To accomplish this, we need a better understanding of how to identify those children at highest risk and the predictors of adverse outcome in these special populations. In 1991 we initiated a study of 8-18 year old high (HR) and low- risk (LR) offspring. The high-risk children/adolescents were from families that were multigenerational for alcoholism affectation (ascertained in a previous award [1984-1990]). These multiplex families had been identified through a pair of alcoholic brothers (child's father and uncle who led us to the full pedigree. Analysis of data from that follow-up (7.5 waves) has provided a number of insights for better understanding the risk factors associated with substance dependence in multigenerational families. HR children have a significantly earlier onset to begin drinking, experience significantly elevated rates of child and adolescent psychopathology, and show evidence of neurodevelopmental delay in achieving age-appropriate levels of P300 amplitude and postural control. Neuroimaging has revealed a lateralized reduction in amygdala volume in HR offspring. Lateralized increases in tissue volume occur during adolescence in limbic areas including the amygdala. Our amygdala results may also point to a neurodevelopmental delay in HR offspring. These markers will ultimately be related to outcome. Our Young Adult follow-up already indicates greatly elevated alcohol dependence in the HR group. The proposed work would include: (1) an 8-18 year old replication sample (N=150) of younger siblings and (2) would extend the Young Adult follow-up to include 361 individuals (many were seen in the child/adolescent follow-up). Consequently, a large number of sibling pairs can be studied using familial resemblance techniques. The existence of a new cohort that includes younger children than are currently being followed would enable us to conduct a longitudinal neuroimaging/P300 study in children before significant drinking has begun and relate this to the expected P300 developmental changes. The replication would include measures previously used in the first 8-18 year old follow-up thus allowing confirmation of our neurodevelopmental delay hypothesis. New measures will be added to explore non-shared environmental effects in these families where sibling pairs are available for study (N=346 sib pairs).